PCSK9 is the 9th member of a family of secretory subtilisin-like serine proteinases known as the proprotein convertases (PCs)1-3. It is now recognized as a major candidate gene for the development of pharmacologically relevant inhibitors or silencers, as it induces an enhanced cellular degradation of the low density lipoprotein receptor (LDLR) in endosomes-lysosomes4,5. An increased activity of PCSK9 would thus result in an upregulation of the level of circulating LDL-cholesterol, one of the major causes of dyslipidemias leading to hypercholesterolemia and atherosclerosis. Indeed, its gene represents the third chromosomal locus of dominant familial hypercholesterolemia6 as was recently reconfirmed in two genetic wide screens7,8 and a liver specific screen9. Both gain and loss of function mutations have been reported for PCSK9 resulting in hyper- and hypo-cholesterolemia, respectively3. Indeed, recent data supported this notion, in either knockout mice10,11 or in transgenic mice overexpressing PCSK9 in liver11.
PCSK9 is the only PC that is secreted as a catalytically inactive prosegment-PC heterodimer2,4,12. Indeed, the enhanced degradation of the LDLR4,5,13,149-11 in endosomes/lysosomes4,15 induced by PCSK9 does not seem to require its catalytic activity12,16. The same seems to apply to the PCSK9-induced degradation of two other LDLR-family members VLDLR and ApoER217. This intriguing twist in the function of this convertase is supported by the crystal structure of PCSK9, which revealed an extended tight binding complex of the enzyme and its inhibitory prosegment18. Indeed, it is this complex that tightly binds the EGF-A repeat of the LDLR19 with increasing strength at the lower pH of endosomes/lysosomes18 that likely leads to the degradation of this tripartite complex by resident hydrolases. Thus, although the zymogen propCSK9 is autocatalytically converted into the inactive heterodimer prosegment-PCSK9 in the ER2,4, so far the only known PCSK9 substrate is itself.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.